RU2003133452A

RU2003133452A - ANALOGUES OF NOCICEPTINE

Info

Publication number: RU2003133452A
Application number: RU2003133452/04A
Authority: RU
Inventors: Кун СУН (US); Кун СУН; Р. Ричард ГЕРИНГ (US); Р. Ричард ГЕРИНГ; Дональд КАЙЛ (US); Дональд Кайл; Чжэньмин ЧЭНЬ (US); Чжэньмин ЧЭНЬ; Сэм ВИКТОРИ (US); Сэм ВИКТОРИ; Джон УАЙТХЕД (US); Джон УАЙТХЕД
Original assignee: Эро-Селтик, С.А. (Lu); Эро-Селтик, С.А.
Priority date: 2001-04-18
Filing date: 2002-04-18
Publication date: 2005-03-27
Also published as: RU2265018C2; RU2005119885A; RU2426730C2

Claims

1. The compound of formula (I):

where D represents a 5-8 membered cycloalkyl, 5-8 membered heterocyclic or 6 membered aromatic or heteroaromatic group;

n represents an integer from 0 to 3;

A, B and Q independently represent hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _1-10 alkoxy, C _3-12 cycloalkoxy, -CH ₂ OH, -NHSO ₂ , hydroxyC _1-10 alkyl- , aminocarbonyl-, C _1-4 alkylaminocarbonyl-, diC _1-4 alkylaminocarbonyl-, acylamino, acylaminoalkyl-, amide, sulfonylaminoC _1-10 alkyl-, or AB together can form a C _2-6 bridge, or BQ together can form a bridge C _3-7 , or AQ together can form a C _1-5 bridge;

Z is selected from the group consisting of a bond, straight or branched C _1-6 alkylene, —NH—, —CH ₂ O—, —CH ₂ NH—, —CH ₂ N (CH ₃ ) -, —NHCH ₂ -, - CH ₂ CONH-, -NHCH ₂ CO-, -CH ₂ CO-, -COCH ₂ -, -CH ₂ COCH ₂ -,

-CH (CH ₃ ) -, -CH =, -O- and -HC = CH-, where the carbon and / or nitrogen atoms are unsubstituted or are substituted by one or more lower alkyl, hydroxy, halogen or alkoxy groups;

R _{1 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _2-10 alkenyl, amino, C _1-10 alkylamino, C _3-12 cycloalkylamino, -COOV ₁ , -C _1-4 COOV ₁ , cyano, cyanoC _1-10 alkyl-, cyanoC _3-10 cycloalkyl-, NH ₂ SO ₂ -, NH ₂ SO ₂ C _1-4 alkyl-, NH ₂ SOC _1-4 alkyl-, aminocarbonyl- , C _1-4 alkylaminocarbonyl-, diC _1-4 alkylaminocarbonyl-, benzyl, C _3-12 cycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro-ring system of formula (V):

where X ₁ and X _{2 are} independently selected from the group consisting of NH, O, S, and CH ₂ ; and wherein said alkyl, cycloalkyl, alkenyl, C _1-10 alkylamino, C _3-12 cycloalkylamino or benzyl from the group R _{1 is} optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C _1-10 alkyl , C _1-10 alkoxy, nitro, trifluoromethyl-, cyano, -COOV ₁ , -C _1-4 COOV ₁ , cyanoC _1-10 alkyl-, -C _1-5 (= O) W ₁ , -C _1-5 NHS (= O) ₂ W ₁ , -C _1-5 NHS (= O) W ₁ , 5-membered heteroaryl C _0-4 alkyl-, phenyl, benzyl, benzyloxy, wherein said phenyl, benzyl and benzyloxy are optionally substituted with 1- 3 substituents selected from the group consisting of halogen,

C _1-10 alkyl-, C _1-10 alkoxy and cyano; and wherein said C _3-12 cycloalkyl, C _3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system or spiro ring system of formula (V) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, where these phenyl, benzyl, phenyloxy or benzyloxy are optionally substituted with 1-3 substituents selected from the group comp consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy and cyano;

W ₁ represents hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _1-10 alkoxy, C _3-12 cycloalkoxy, -CH ₂ OH, amino, C _1-4 alkylamino, diC _1-4 alkylamino or A 5 membered heteroaromatic ring optionally substituted with 1 to 3 lower alkyls;

V ₁ represents H, C _1-6 alkyl, C _3-6 cycloalkyl, benzyl or phenyl;

R _{2 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl and halogen, wherein said alkyl or cycloalkyl is optionally substituted with oxo, amino, alkylamino or dialkylamino;

or its pharmaceutically acceptable salts or solvates.

2. The compound according to claim 1, in which D represents phenyl or a 6-membered heteroaromatic group containing 1-3 nitrogen atoms.

3. The compound according to claim 1, in which ZR ₁ represents cyclohexylethyl, cyclohexylmethyl, cyclopentylmethyl, dimethylcyclohexylmethyl, phenylethyl, pyrrolyl trifluoroethyl,

thienyl trifluoroethyl-, pyridylethyl-, cyclopentyl-, cyclohexyl-, methoxycyclohexyl-, tetrahydropyranyl-, propylpiperidinyl-, indolylmethyl-, pyrazolylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-yloxyloxypropyl

4. The compound according to claim 1, in which ZR ₁ is —CH ₂ COOV ₁ , tetrazolylmethyl, cyanomethyl, NH ₂ SO ₂ methyl, NH ₂ SO methyl, aminocarbonylmethyl, C _1-4 alkylaminocarbonylmethyl or diC _{1- 4} alkylaminocarbonylmethyl-.

5. The compound according to claim 1, in which ZR ₁ is 3,3-diphenylpropyl, optionally substituted at 3 carbon atoms, propyl group -COOV ₁ , tetrazolyl C _0-4 alkyl-, cyano-, aminocarbonyl-, C _1-4 alkylaminocarbonyl- or diC _1-4 alkylaminocarbonyl.

6. The compound of formula (IA):

where n represents an integer from 0 to 3;

Z is selected from the group consisting of, —CH ₂ -, —NH—, —CH ₂ O—, CH ₂ CH ₂ , —CH ₂ NH—, —CH ₂ N (CH ₃ ) -, —NHCH ₂ -, -CH ₂ CONH-, -NHCH ₂ CO-, -CH ₂ CO-, -COCH ₂ -, -CH ₂ COCH ₂ -, -CH (CH ₃ ) -, -CH = and -HC = CH-, where the atoms carbon and / or nitrogen are unsubstituted or substituted with lower alkyl, halogen, hydroxy or alkoxy;

R _{1 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _2-10 alkenyl, amino, C _1-10 alkylamino, C _3-12 cycloalkylamino, benzyl, C _3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system, and spiro-ring system of formula (V):

in which X ₁ and X _{2 are} independently selected from the group consisting of NH, O, S and CH ₂ ;

wherein said alkyl, cycloalkyl, alkenyl, C _1-10 alkylamino, C _3-12 cycloalkylamino or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, nitro , trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, wherein said phenyl, benzyl and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy and cyano;

wherein said C _3-12 cycloalkyl, C _3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl,

heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro ring system of formula (V) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, nitro, trifluoromethyl, phenyl benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy and cyano;

R _{2 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl and halogen, wherein said alkyl is optionally substituted with an oxo group;

or its pharmaceutically acceptable salts.

7. The compound according to claim 6, in which R ₁ represents an alkyl selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl and hexyl.

8. The compound according to claim 6, in which R ₁ represents a cycloalkyl selected from the group consisting of cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl or norbornyl.

9. The compound according to claim 6, in which R ₁ represents tetrahydronaphthyl, decahydronaphthyl or dibenzocycloheptyl.

10. The compound according to claim 6, in which r ₁ represents phenyl or benzyl.

11. The compound according to claim 6, in which r ₁ represents a bicyclic aromatic ring.

12. The compound of claim 11, wherein said bicyclic aromatic ring is indenyl, quinoline or naphthyl.

13. The compound according to claim 11, in which Z represents a bond, methyl or ethyl.

14. The compound according to claim 6, in which n is 0.

15. The compound according to claim 6, in which X ₁ and X ₂ both represent O.

16. A compound selected from the group consisting of:

3- [1- (naphth-2-ylmethyl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (naphth-1-ylmethyl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (p-phenylbenzyl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (p-benzyloxybenzyl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (p-cyanobenzyl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (3,3-diphenylpropyl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- [4,4-bis- (4-fluorophenyl) butyl] -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (2-phenylethyl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (cyclooctylmethyl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (1,2,3,4-tetrahydro-2-naphthyl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (5-methylhex-2-yl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5-yl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (4-propylcyclohexyl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (norbornan-2-yl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (decahydro-2-naphthyl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (3,3-dimethyl-1,5-dioxaspiro [5.5] undeca-9-yl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- [4- (1-methylethyl) cyclohexyl] -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (1,3-dihydroinden-2-yl) -4-piperidinyl] -2H-benzoxazol-2-one;

3- [1- (cyclooctyl) -4-piperidinyl] -2H-benzoxazol-2-one; and

their pharmaceutically acceptable salts.

17. A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable excipient.

18. A method of treating pain, comprising administering to a patient in need thereof an effective amount of an analgesic compound according to claim 1.

19. A method of modulating the pharmacological response from the ORL1 receptor, comprising administering to a patient in need thereof an effective amount of a compound according to claim 1.

20. A pharmaceutical composition comprising a compound according to claim 6 and at least one pharmaceutically acceptable excipient.

21. A method of treating pain, comprising administering to a patient in need thereof an effective amount of an analgesic compound according to claim 6.

22. A method of modulating the pharmacological response from the ORL1 receptor, comprising administering an effective amount of a compound according to claim 6.

23. The compound of formula (IA):

where R _{2 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl and halogen, wherein said alkyl is optionally substituted with an oxo group;

n represents an integer from 0 to 3;

ZR ₁ represents the following

where Y ₁ represents R ₃ - (C ₁ -C ₁₂ ) alkyl, R ₄ aryl, R ₅ heteroaryl, R ₆ - (C ₃ -C ₁₂ ) cycloalkyl, R ₇ - (C ₃ -C ₇ ) heterocycloalkyl, —CO ₂ (C ₁ -C ₆ ) alkyl, CN or —C (O) NR ₈ R ₉ ; Y ₂ represents hydrogen or Y ₁ ; Y ₃ represents hydrogen or (C ₁ -C ₆ ) alkyl; or Y ₁ , Y ₂ and Y ₃ together with the carbon atom to which they are bonded form one of the following structures:

or

where r is 0-3; w and u each is 0-3, provided that the sum of w and u is 1-3; c and d are each independently 1 or 2; s is 1-5; and ring E is a fused R ₄ phenyl or R ₅ heteroaryl ring;

R ₁₀ represents 1-3 substituents independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, -OR ₈ , - (C ₁ -C ₆ ) alkyl-OR ₈ , -NR ₈ R ₉ and - (C ₁ -C ₆ ) alkyl-NR ₈ R ₉ ;

R ₁₁ represents 1-3 substituents independently selected from the group consisting of R ₁₀ , —CF ₃ , —OCF ₃ , NO ₂ and halogen, or R ₁₁ substituents on adjacent ring carbon atoms together can form a methylenedioxy or ethylenedioxy ring;

R ₈ and R _{9 are} independently selected from the group consisting of hydrogen, (C ₁ -C ₆ ) alkyl, (C ₃ -C ₁₂ ) cycloalkyl, aryl and aryl (C ₁ -C ₆ ) alkyl;

R ₃ represents 1-3 substituents independently selected from the group consisting of H, R ₄ aryl, R ₆ - (C ₃ -C ₁₂ ) cycloalkyl, R ₅ -heteroaryl, R ₇ - (C ₃ -C ₇ ) heterocycloalkyl , -NR ₈ R ₉ , -OR ₁₂ and -S (O) _0-2 R ₁₂ ;

R ₆ represents 1-3 substituents independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, R ₄ aryl, —NR ₈ R ₉ , —OR ₁₂ and —SR ₁₂ ;

R ₄ represents 1-3 substituents independently selected from the group consisting of hydrogen, halogen, (C ₁ -C ₆ ) alkyl, R ₁₃ aryl, (C ₃ -C ₁₂ ) cycloalkyl, —CN, —CF ₃ , - OR ₈ , - (C ₁ -C ₆ ) alkyl-OR ₈ , -OCF ₃ , -NR ₈ R ₉ , - (C ₁ -C ₆ ) alkyl-NR ₈ R ₉ , -NHSO ₂ R ₈ , -SO ₂ N (R ₁₄ ) ₂ , -SO ₂ R ₈ , -SOR ₈ , -SR ₈ , -NO ₂ , -CONR ₈ R ₉ , -NR ₉ COR ₈ , -COR ₈ , -COCF ₃ , -OCOR ₈ , - OCO ₂ R ₈ , -COOR ₈ , - (C ₁ -C ₆ ) alkyl-NHCOOC (CH ₃ ) ₃ , - (C ₁ -C ₆ ) alkyl-NHCOCF ₃ , - (C ₁ -C ₆ ) alkyl-NHSO ₂ - (C ₁ -C ₆ ) alkyl, - (C ₁ -C ₆ ) alkyl-NHCONH- (C ₁ -C ₆ ) -alkyl and

where f is 0-6; or R ₄ substituents on adjacent ring carbon atoms together may form a methylenedioxy or ethylenedioxy ring;

R ₅ represents 1-3 substituents independently selected from the group consisting of hydrogen, halogen, (C ₁ -C ₆ ) alkyl, R ₁₃ aryl, (C ₃ -C ₁₂ ) cycloalkyl, —CN, —CF ₃ , - OR ₈ , - (C ₁ -C ₆ ) alkyl-OR ₈ , -OCF ₃ , -NR ₈ R ₉ , - (C ₁ -C ₆ ) alkyl-NR ₈ R ₉ , -NHSO ₂ R ₈ , -SO ₂ N (R ₁₄ ) ₂ , -NO ₂ , -CONR ₈ R ₉ , -NR ₉ COR ₈ , -COR ₈ , -OCOR ₈ , -OCO ₂ R ₈ and -COOR ₈ ;

R ₇ represents H, (C ₁ -C ₆ ) alkyl, -OR ₈ , - (C ₁ -C ₆ ) alkyl-OR ₈ , -NR ₈ R ₉ or - (C ₁ -C ₆ ) alkyl-NR ₈ R ₉ ;

R ₁₂ represents H, (C ₁ -C ₆ ) alkyl, R ₄ -aryl, - (C ₁ -C ₆ ) alkyl-OR ₈ , - (C ₁ -C ₆ ) alkyl-NR ₈ R ₉ , - (C ₁ -C ₆ ) alkyl-SR ₈ or aryl (C ₁ -C ₆ ) alkyl;

R ₁₃ represents 1-3 substituents independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy and halogen;

R _{14 is} independently selected from the group consisting of H, (C ₁ -C ₆ ) alkyl and R ₁₃ -C ₆ H ₄ -CH ₂ -;

or its pharmaceutically acceptable salts.

24. A pharmaceutical composition comprising the compound of claim 23 and at least one pharmaceutically acceptable excipient.

25. A method of treating pain, comprising administering to a patient in need thereof an effective amount of an analgesic compound according to claim 23.

26. A method of modulating the pharmacological response from the ORL1 receptor, comprising administering to a patient in need thereof an effective amount of a compound according to claim 23.

27. A method of modulating the pharmacological response from an opioid receptor, comprising administering to a patient in need thereof an effective amount of a compound according to claim 1.

28. A method of modulating the pharmacological response from an opioid receptor, comprising administering to a patient in need thereof an effective amount of a compound according to claim 6.

29. A method of modulating the pharmacological response from an opioid receptor, comprising administering to a patient in need thereof an effective amount of a compound according to claim 23.

30. The compound of formula (II):

where the dotted line represents an optional double bond;

R represents hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _3-12 cycloalkyl C _1-4 alkyl, C _1-10 alkoxy, C _3-12 cycloalkoxy, C _1-10 alkenyl, C _1-10 alkylidene, oxo, C _1-10 alkyl substituted with 1-3 halogens, C _3-12 cycloalkyl substituted with 1-3 halogens, C _3-12 cycloalkyl C _1-4 alkyl- substituted with 1-3 halogens, C _1-10 alkoxy substituted with 1-3 halogens, C _3-12 cycloalkoxy-, substituted with 1-3 halogens, -COOV ₁ , -C _1-4 COOV ₁ , -CH ₂ OH, -SO ₂ N (V ₁ ) ₂ , hydroxyC _{1- 10} alkyl, hydroxyC _3-10 cycloalkyl, cyanoC _1-10 alkyl, cyanoC _3-10 cycloalkyl, -CON (V ₁ ) ₂ , NH ₂ SO ₂ C _1-4 alkyl, NH ₂ SOC _1-4 alkyl, sulfonylamino C _1-10 alkyl, diaminoalkyl, sul fonilC _1-4 alkyl, a 6-membered heterocyclic ring, a 6-membered heteroaromatic ring, a 6-membered geterotsiklilC _1-4 alkyl-, a 6-membered geteroarilC _1-4 alkyl-, a 6-membered aromatic ring, a 6-membered _1- arilC ₄ alkyl, 5-membered heterocyclic ring, optionally substituted oxo or thio, 5-membered heteroaromatic ring,

5-membered heterocyclyl C _1-4 alkyl- optionally substituted with oxo or thio, 5-membered heteroaryl C _1-4 alkyl-, -C _1-5 (= O) W ₁ , -C _1-5 (= NH) W ₁ , -C _1-5 NHC (= O) W ₁ , -C _1-5 NHS (= O) ₂ W ₁ , -C _1-5 NHS (= O) W ₁ , where W ₁ represents hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _1-10 alkoxy, C _3-12 cycloalkoxy, -CH ₂ OH, amino, C _1-4 alkylamino, diC _1-4 alkylamino or 5 membered heteroaromatic ring, optionally substituted with 1 -3 lower alkyls;

where each V _{1 is} independently selected from H, C _1-6 alkyl, C _3-6 cycloalkyl, benzyl and phenyl;

n represents an integer from 0 to 3;

D represents a 5-8 membered cycloalkyl, 5-8 membered heterocyclic or 6 membered aromatic or heteroaromatic group;

n represents an integer from 0 to 3;

A, B and Q independently represent hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _1-10 alkoxy, C _3-12 cycloalkoxy, C _1-10 alkenyl, C _1-10 alkylidene, oxo, - CH ₂ OH, -NHSO ₂ , hydroxyC _1-10 alkyl-, aminocarbonyl-, C _1-4 alkylaminocarbonyl-, diC _1-4 alkylaminocarbonyl-, acylamino-, acylaminoalkyl-, amide, sulfonylaminoC _1-10 alkyl-, or AB together can form a C _2-6 bridge, or BQ together can form a C _3-7 bridge, or AQ together can form a C _1-5 bridge;

Z is selected from the group consisting of a bond, straight or branched C _1-6 alkylene, —NH—, —CH ₂ O—, —CH ₂ NH—, —CH ₂ N (CH ₃ ) -, —NHCH ₂ -, - CH ₂ CONH-, -NHCH ₂ CO-, -CH ₂ CO-, -COCH ₂ -, -CH ₂ COCH ₂ -, -CH (CH ₃ ) -, -CH =, -O- and -HC = CH- where the carbon and / or nitrogen atoms are unsubstituted or substituted by one or more

lower alkyl, hydroxy, halogen or alkoxy groups;

R _{1 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _2-10 alkenyl, amino, C _1-10 alkylamino, C _3-12 cycloalkylamino, -COOV ₁ , -C _1-4 COOV ₁ , cyano, cyanoC _1-10 alkyl-, cyanoC _3-10 cycloalkyl-, NH ₂ SO ₂ -, NH ₂ SO ₂ C _1-4 alkyl-, NH ₂ SOC _1-4 alkyl-, aminocarbonyl- , C _1-4 alkylaminocarbonyl, diC _1-4 alkylaminocarbonyl, benzyl, C _3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro ring system of formula (V):

where X ₁ and X _{2 are} independently selected from the group consisting of NH, O, S, and CH ₂ ; and wherein said alkyl, cycloalkyl, alkenyl, C _1-10 alkylamino, C _3-12 cycloalkylamino or benzyl from the group R _{1 is} optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C _1-10 alkyl , C _1-10 alkoxy, nitro, trifluoromethyl-, cyano, -COOV ₁ , -C _1-4 COOV ₁ , cyanoC _1-10 alkyl-, -C _1-5 (= O) W ₁ , -C _1-5 NHS (= O) ₂ W ₁ , -C _1-5 NHS (= O) W ₁ , 5-membered heteroaryl C _0-4 alkyl-, phenyl, benzyl, benzyloxy, wherein said phenyl, benzyl and benzyloxy are optionally substituted with 1- 3 substituents selected from the group consisting of halogen, C _1-10 alkyl-, C _1-10 alkoxy and cyano; and wherein said C _3-12 cycloalkyl, C _3-12 cycloalkenyl, monocyclic, bicyclic

or a tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and the spiro ring system of formula (V) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, nitro , trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy and cyano ;

or its pharmaceutically acceptable salts or solvates.

31. The compound according to item 30, in which D represents phenyl or a 6-membered heteroaromatic group containing 1-3 nitrogen atoms.

32. The compound of claim 30, wherein R is selected from the group consisting of —CH ₂ C = ONH ₂ , —C (NH) NH ₂ , pyridylmethyl, cyclopentyl, cyclohexyl, furanylmethyl, —C = OCH ₃ , —CH ₂ CH ₂ NHC = OCH ₃ , —SO ₂ CH ₃ , CH ₂ CH ₂ NHSO ₂ CH ₃ , furanylcarbonyl-, methylpyrrolylcarbonyl-, diazolcarbonyl-, azolmethyl-, trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxooxazolmethyl- and diazolmethyl-.

33. The compound of claim 30, wherein ZR _{1 is} selected from the group consisting of cyclohexyl ethyl, cyclohexyl methyl, cyclopentyl methyl, dimethylcyclohexyl methyl, phenylethyl, pyrrolyl trifluoroethyl, thienyl trifluoroethyl, pyridylethyl,

cyclopentyl-, cyclohexyl-, methoxycyclohexyl-, tetrahydropyranyl-, propylpiperidinyl-, indolylmethyl-, pyrazolylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl-, hexyl.

34. The compound of claim 30, wherein at least one of ZR ₁ and R is selected from the group consisting of —CH ₂ COOV ₁ , tetrazolylmethyl-, cyanomethyl-, NH ₂ SO ₂ methyl-, NH ₂ SOmethyl-, aminocarbonylmethyl -, C _1-4 alkylaminocarbonylmethyl- and diC _1-4 alkylaminocarbonylmethyl-.

35. The compound of claim 30, wherein ZR ₁ is 3,3-diphenylpropyl, optionally substituted at 3 carbon atoms with a propyl group -COOV ₁ , tetrazolyl C _0-4 alkyl-, cyano-, aminocarbonyl-, C _1-4 alkylaminocarbonyl- or diC _1-4 alkylaminocarbonyl.

36. The compound of formula (IIA):

where the dotted line represents an optional double bond;

Z is selected from the group consisting of, —CH ₂ -, —NH—, —CH ₂ O—, —CH ₂ CH ₂ -, —CH ₂ NH—, —CH ₂ N (CH ₃ ) -, —NHCH ₂ -, -CH ₂ CONH-, -NHCH ₂ CO-, -CH ₂ CO-, -COCH ₂ -, -CH ₂ COCH ₂ -, -CH (CH ₃ ) -, -CH = and -HC = CH-, where the carbon and / or nitrogen atoms are unsubstituted or substituted by a lower alkyl, hydroxy, halogen or alkoxy group;

R and Q are the same or different and each is selected from the group consisting of hydrogen, halogen, C _1-10 alkyl, C _1-10 alkenyl, C _1-10 alkylidene, C _3-12 cycloalkyl, C _1-10 alkoxy and oxo ;

R _{1 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _2-10 alkenyl, amino, C _1-10 alkylamino, C _3-12 cycloalkylamino, benzyl, C _3-12 cycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring, bicyclic ring system and spiro-ring system of formula (V):

wherein said alkyl, cycloalkyl, alkenyl, C _1-10 alkylamino, C _3-12 cycloalkylamino or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, nitro , trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, wherein phenyl, benzyl and

benzyloxy is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy and cyano;

wherein said C _3-12 cycloalkyl, C _3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro ring system of formula (V) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting yaschey of halogen, C _1-10 alkyl, C _1-10 alkoxy, and cyano;

or its pharmaceutically acceptable salts.

37. The compound of claim 36, wherein Q is hydrogen or methyl.

38. The compound according to clause 36, in which R represents hydrogen, methyl, ethyl or ethylidene.

39. The compound of claim 36, wherein R ₁ is alkyl selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, or hexyl.

40. The compound of claim 36, wherein R ₁ is cycloalkyl selected from the group consisting of cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and

norbornyl.

41. The compound according to clause 36, in which R ₁ represents tetrahydronaphthyl, decahydronaphthyl or dibenzocycloheptyl.

42. The compound according to clause 36, in which R ₁ represents phenyl or benzyl.

43. The compound according to clause 36, in which R ₁ represents a bicyclic aromatic ring.

44. The compound of claim 43, wherein said bicyclic aromatic ring is indenyl, quinoline or naphthyl.

45. The compound according to clause 36, in which Z represents a bond, methyl or ethyl.

46. The compound of claim 36, wherein n is O.

47. The compound according to clause 36, in which X ₁ and X ₂ both represent O.

48. The compound of claim 36, wherein the dotted line represents a double bond.

49. A compound selected from the group consisting of:

3-ethylidene-1- [1- (5-methylhex-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethylidene-1- [1- (4-propylcyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethylidene-1- [1- (1,2,3,4-tetrahydro-2-naphthyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethylidene-1- [1- (1,3-dihydroinden-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethylidene-1- [1- (naphth-2-ylmethyl) -4-piperidinyl] -1,3-dihydro

2H-indol-2-one;

3-ethylidene-1- [1- (p-benzyloxybenzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethylidene-1- [1- (benzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethylidene-1- [1- (cyclooctylmethyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethylidene-1- [1- (norbornan-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethylidene-1- [1- (3,3-diphenylpropyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethylidene-1- [1- (p-cyanobenzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- (5-methylhex-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- [4- (1-methylethyl) cyclohexyl] -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- (4-propylcyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- (1,2,3,4-tetrahydro-2-naphthyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- (decahydro-2-naphthyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- (1,3-dihydroinden-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- (cyclooctylmethyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- (norbornan-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

1- [1- (naphth-1-ylmethyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

1- [1- (naphth-2-ylmethyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

1- [1- (p-phenylbenzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

1- [1- (3,3-bis (phenyl) propyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

1- [1- (p-cyanobenzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

1- [1- (p-benzyloxybenzyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

1- [1- (1,2,3,4-tetrahydronaphth-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

1- [1- (5-methylhex-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

1- [1- (norbornan-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

1- [1- (1,3-dihydroinden-2-yl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

1- [1- (cyclooctylmethyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

1- [1- (benzyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

1- [1- (4-propylcyclohexyl) -3- (methyl) -4-piperidinyl] -1.3-

dihydro-2H-indol-2-one;

1- [1- (5-methylhex-2-yl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

1- [1- (decahydro-2-naphthyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

1- [1- (4- (1-methylethyl) cyclohexyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

1- [1- (cyclooctylmethyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

1- [1- (3,3-bis (phenyl) propyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- (3,3-bis (phenyl) propyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- (4-propylcyclohexyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- (5-methylhex-2-yl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- [4- (1-methylethyl) cyclohexyl] -3-methyl-4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

3-ethyl-1- [1- (decahydro-2-naphthyl) -3- (methyl) -4-piperidinyl] -1,3-dihydro-2H-indol-2-one;

and its pharmaceutically acceptable salts.

50. A pharmaceutical composition comprising a compound of claim 30 and at least one pharmaceutically acceptable excipient.

51. A method of treating pain, comprising administering to a patient in need thereof an effective amount of an analgesic

compounds according to claim 30.

52. A method for modulating the pharmacological response from the ORL1 receptor, comprising administering to a patient in need thereof an effective amount of a compound according to claim 30.

53. A pharmaceutical composition comprising a compound according to claim 36 and at least one pharmaceutically acceptable excipient.

54. A method of treating pain, comprising administering to a patient in need thereof an effective amount of an analgesic compound according to claim 36.

55. A method of modulating the pharmacological response from the ORL1 receptor, comprising administering an effective amount of a compound according to claim 36.

56. The compound of formula (IIA):

where the dotted line represents an optional double bond;

R and Q are the same or different and each is selected from

a group consisting of hydrogen, halogen, C _1-10 alkyl, C _1-10 alkenyl, C _1-10 alkylidene, C _3-12 cycloalkyl, C _1-10 alkoxy and oxo;

ZR ₁ represents

,

or

R ₄ represents 1-3 substituents independently selected from the group consisting of hydrogen, halogen, (C ₁ -C ₆ ) alkyl, R ₁₃ aryl, (C ₃ -C ₁₂ ) cycloalkyl, —CN, —CF ₃ , - OR ₈ , - (C ₁ -C ₆ ) alkyl-OR ₈ , -OCF ₃ ,

-NR ₈ R ₉ , - (C ₁ -C ₆ ) alkyl-NR ₈ R ₉ , -NHSO ₂ R ₈ , -SO ₂ N (R ₁₄ ) ₂ , -SO ₂ R ₈ , -SOR ₈ , -SR ₈ , -NO ₂ , -CONR ₈ R ₉ , -NR ₉ COR ₈ , -COR ₈ , -COCF ₃ , -OCOR ₈ , -OCO ₂ R ₈ , -COOR ₈ , - (C ₁ -C ₆ ) alkyl-NHCOOC (CH ₃ ) ₃ , - (C ₁ -C ₆ ) alkyl-NHCOCF ₃ , - (C ₁ -C ₆ ) alkyl-NHSO ₂ - (C ₁ -C ₆ ) alkyl, - (C ₁ -C ₆ ) alkyl -NHCONH- (C ₁ -C ₆ ) -alkyl and

or its pharmaceutically acceptable salts.

57. A pharmaceutical composition comprising a compound of claim 56 and at least one pharmaceutically acceptable excipient.

58. A method of treating pain, comprising administering to a patient in need thereof an effective amount of an analgesic compound according to claim 56.

59. A method for modulating the pharmacological response from the ORL1 receptor, comprising administering to a patient in need thereof an effective amount of a compound according to claim 56.

60. A method of modulating the pharmacological response from an opioid receptor, comprising administering to a patient in need thereof an effective amount of a compound according to claim 30.

61. A method of modulating the pharmacological response from an opioid receptor, comprising administering to a patient in need thereof an effective amount of a compound according to claim 36.

62. A method of modulating the pharmacological response from an opioid receptor, comprising administering to a patient in need thereof an effective amount of a compound according to claim 56.

63. The compound of formula (III):

where R is hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _3-12 cycloalkyl C _1-4 alkyl, C _1-10 alkoxy, C _3-12 cycloalkoxy, C _1-10 alkyl, substituted 1- 3 halogens, C _3-12 cycloalkyl substituted

1-3 halogens, C _3-12 cycloalkyl C _1-4 alkyl, substituted with 1-3 halogens, C _1-10 alkoxy, substituted with 1-3 halogens, C _3-12 cycloalkoxy, substituted with 1-3 halogens, -COOV ₁ , -C _1-4 COOV ₁ , -CH ₂ OH, -SO ₂ N (V ₁ ) ₂ , hydroxyC _1-10 alkyl-, hydroxyC _3-10 cycloalkyl-, cyanoC _1-10 alkyl-, cyanoC _3-10 cycloalkyl -, -CON (V ₁ ) ₂ , NH ₂ SO ₂ C _1-4 alkyl, NH ₂ SOC _1-4 alkyl, sulfonylamino C _1-10 alkyl, diaminoalkyl, sulfonyl C _1-4 alkyl, 6 membered heterocyclic ring, a 6-membered heteroaromatic ring, a 6-membered geterotsiklilC _1-4 alkyl-, a 6-membered geteroarilC _1-4 alkyl-, a 6-membered aromatic ring, a 6-membered arilC _1-4 lkil-, 5-membered heterocyclic ring optionally substituted with an oxo or thio, a 5-membered heteroaromatic ring, a 5-membered geterotsiklilC _1-4 alkyl- optionally substituted with an oxo or thio, a 5-membered geteroarilC _1-4 alkyl-, -C _{1 -5} (= O) W ₁ , -C _1-5 (= NH) W ₁ , -C _1-5 NHC (= O) W ₁ , -C _1-5 NHS (= O) ₂ W ₁ , -C _1-5 NHS (= O) W ₁ , where W ₁ represents hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _1-10 alkoxy, C _3-12 cycloalkoxy, -CH ₂ OH, amino, C _{1 -4} alkylamino, diC _1-4 alkylamino or 5-membered heteroaromatic ring, optionally substituted with 1-3 lower alkyls;

n represents an integer from 0 to 3;

Z is selected from the group consisting of a bond, straight or branched C _1-6 alkylene, —NH—, —CH ₂ O—, —CH ₂ NH—, —CH ₂ N (CH ₃ ) -,

-NHCH ₂ -, -CH ₂ CONH-, -NHCH ₂ CO-, -CH ₂ CO-, -COCH ₂ -, -CH ₂ COCH ₂ -, -CH (CH ₃ ) -, -CH =, -O- and —HC = CH—, where the carbon and / or nitrogen atoms are unsubstituted or substituted by one or more lower alkyl, hydroxy, halogen or alkoxy groups; or Z represents a cycloalkylamine system of formula (VI):

where A, B and Q are independently hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _1-10 alkoxy, C _3-12 cycloalkoxy, -CH ₂ OH, -NHSO ₂ , hydroxyC _1-10 alkyl -, aminocarbonyl-, C _1-4 alkylaminocarbonyl-, diC _1-4 alkylaminocarbonyl-, acylamino, acylaminoalkyl-, amide, sulfonylamino C _1-10 alkyl-, or AB together can form a C _2-6 bridge, or BQ together can form bridge C _3-7 , or AQ together can form bridge C _1-5 ;

R _{1 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _{3 * -12} cycloalkyl, C _2-10 alkenyl, amino, C _1-10 alkylamino, C _3-12 cycloalkylamino, -COOV ₁ , - C _1-4 COOV ₁ , cyano, cyano C _1-10 alkyl-, cyano C _3-10 cycloalkyl-, NH ₂ SO ₂ -, NH ₂ SO ₂ C _1-4 alkyl-, NH ₂ SOC _1-4 alkyl-, aminocarbonyl -, C _1-4 alkylaminocarbonyl-, diC _1-4 alkylaminocarbonyl-, benzyl, C _3-12 cycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro-ring system

formulas (V):

where X ₁ and X _{2 are} independently selected from the group consisting of NH, O, S, and CH ₂ ; and wherein said alkyl, cycloalkyl, alkenyl, C _1-10 alkylamino, C _3-12 cycloalkylamino or benzyl from the group R _{1 is} optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C _1-10 alkyl , C _1-10 alkoxy, nitro, trifluoromethyl-, cyano, -COOV ₁ , -C _1-4 COOV ₁ , cyanoC _1-10 alkyl-, -C _1-5 (= O) W ₁ , -C _1-5 NHS (= O) ₂ W ₁ , -C _1-5 NHS (= O) W ₁ , 5-membered heteroaryl C _0-4 alkyl-, phenyl, benzyl, benzyloxy, wherein said phenyl, benzyl and benzyloxy are optionally substituted with 1- 3 substituents selected from the group consisting of halogen, C _1-10 alkyl-, C _1-10 alkoxy and cyano; and wherein said C _3-12 cycloalkyl, C _3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro ring system of formula (V) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, in which these phenyl, benzyl, phenyloxy or benzyloxy are optionally substituted with 1-3 substituents selected from the group , tinuous from halogen, C _1-10 alkyl, C _1-10 alkoxy, and cyano;

R ₂ selected from the group consisting of hydrogen, C _1-10 alkyl,

C _3-12 cycloalkyl and halogen, wherein said alkyl or cycloalkyl is optionally substituted with oxo, amino, alkylamino or dialkylamino;

or its pharmaceutically acceptable salts or solvates.

64. The compound according to item 63, in which D represents a phenyl or 6-membered heteroaromatic group containing 1-3 nitrogen atoms.

65. The compound of claim 63, wherein R is selected from the group consisting of —CH ₂ C = ONH ₂ , —C (NH) NH ₂ , pyridylmethyl, cyclopentyl, cyclohexyl, furanylmethyl, —C = OCH ₃ , —CH ₂ CH ₂ NHC = OCH ₃ , —SO ₂ CH ₃ , CH ₂ CH ₂ NHSO ₂ CH ₃ , furanylcarbonyl-, methylpyrrolylcarbonyl-, diazolcarbonyl-, azolmethyl-, trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxooxazolmethyl- and diazolmethyl-.

66. The compound of claim 63, wherein ZR _{1 is} selected from the group consisting of cyclohexyl ethyl, cyclohexylmethyl, cyclopentylmethyl, dimethylcyclohexylmethyl, phenylethyl, pyrrolyl trifluoroethyl, thienyl trifluoroethyl, pyridylethyl, cyclopentyl-cyclohexyl, cyclohexyl , tetrahydropyranyl-, propylpiperidinyl-, indolylmethyl-, pyrazolylpentyl-, thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-, isopropoxybutyl-, hexyl- or oxocanylpropyl-.

67. The compound of claim 63, wherein at least one of ZR ₁ and R is selected from the group consisting of —CH ₂ COOV ₁ , tetrazolylmethyl-, cyanomethyl-, NH ₂ SO ₂ methyl-, NH ₂ SOmethyl-, aminocarbonylmethyl -, C _1-4 alkylaminocarbonylmethyl- and diC _1-4 alkylaminocarbonylmethyl-.

68. The compound of claim 63, wherein ZR ₁ is 3,3-diphenylpropyl optionally substituted at 3 carbon atoms with propyl group -COOV ₁ , tetrazolyl C _0-4 alkyl-, cyano-, aminocarbonyl-, C _1-4 alkylaminocarbonyl- or diC _1-4 alkylaminocarbonyl.

69. The compound of formula (IIIA):

where n represents an integer from 0 to 3;

Z is selected from the group consisting of, —CH ₂ -, —NH—, —CH ₂ O—, —CH ₂ CH ₂ -, —CH ₂ NH—, —CH ₂ N (CH ₃ ) -, —NHCH ₂ -, -CH ₂ CONH-, -NHCH ₂ CO-, -CH ₂ CO-, -COCH ₂ -, -CH ₂ COCH ₂ -, -CH (CH ₃ ) -, -CH =, -HC = CH- and cycloalkylamine systems of formula (VI):

in which the carbon and / or nitrogen atoms are unsubstituted or substituted with lower alkyl, halogen, hydroxy, phenyl, benzyl or alkoxy;

R is selected from the group consisting of hydrogen, C _1-10 alkyl, C _1-10 alkoxy and C _3-12 cycloalkyl;

R _{1 is} selected from the group consisting of hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _2-10 alkenyl, amino, C _1-10 alkylamino, C _3-12 cycloalkylamino, benzyl, C _3-12 cycloalkenyl-, monocyclic, bicyclic or tricyclic aryl or heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro-ring system of formula (V):

wherein said alkyl, cycloalkyl, alkenyl, C _1-10 alkylamino, C _3-12 cycloalkylamino or benzyl is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy, wherein said phenyl, benzyl and benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy and cyano;

wherein said C _3-12 cycloalkyl, C _3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro ring system

Formulas (V) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, nitro, trifluoromethyl, phenyl, benzyl, phenyloxy and benzyloxy, where said phenyl, benzyl, phenyloxy and benzyloxy is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy and cyano;

or its pharmaceutically acceptable salts.

70. The compound of claim 69, wherein R ₁ is alkyl selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl.

71. The compound of claim 69, wherein R ₁ is cycloalkyl selected from the group consisting of cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and norbornyl.

72. The compound of claim 69, wherein R ₁ is tetrahydronaphthyl, decahydronaphthyl or dibenzocycloheptyl.

73. The compound of claim 69, wherein R ₁ is phenyl or benzyl.

74. The compound of claim 69, wherein R ₁ is a bicyclic aromatic ring.

75. The compound of claim 74, wherein said bicyclic aromatic ring is indenyl, quinoline or naphthyl.

76. The compound of claim 69, wherein Z is a bond,

methyl or ethyl.

77. The compound of claim 69, wherein n is 0.

78. The compound of claim 69, wherein X ₁ and X ₂ both represent O.

79. The compound of claim 69, wherein Z is a cycloalkylamine system of formula (VI).

80. The compound of claim 69, selected from the group consisting of:

3-ethyl-1- (p-phenylbenzyl) -1,3-dihydro-2H-benzimidazol-2-one;

3-ethyl-1- (5-methylhex-2-yl) -1,3-dihydro-2H-benzimidazol-2-one;

3-ethyl-1- (4-propylcyclohexyl) -1,3-dihydro-2H-benzimidazol-2-one;

3-ethyl-1- (decahydro-2-naphthyl) -1,3-dihydro-2H-benzimidazol-2-one;

3-ethyl-1- (naphth-2-ylmethyl) -1,3-dihydro-2H-benzimidazol-2-one;

1- (p-benzyloxybenzyl) -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;

1-benzyl-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4- (benzylamino) cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;

3-ethyl-1- (naphthylmethyl) -1,3-dihydro-2H-benzimidazol-2-one;

3-ethyl-1- [5- (3-fluorophenyl) -5- (4-fluorophenyl) hexyl] -1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(naphth-2-ylmethyl) ethylamino] cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one;

1- [4- (norbornan-2-ylamino) cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [[4- (1-methylethyl) cyclohexyl] amino] cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(decahydro-2-naphthyl) amino] cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one;

1- [4- (ethylamino) cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one;

1- [4- (benzylamino) cyclohexyl] -1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(indan-2-yl) benzylamino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(cyclooctylmethyl) amino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(naphth-2-yl) amino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(p-benzyloxybenzyl) amino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(decahydro-2-naphthyl) amino] cyclohexyl] -3-ethyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4- (benzylamino) cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4- (dibenzylamino) cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(p-phenylbenzyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(1,2,3,4-tetrahydronaphthyl) amino] cyclohexyl] -5-

carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(4-propylcyclohexyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(5-methylhex-2-yl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(decahydro-2-naphthyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4- (cyclooctylamino) cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(indan-2-yl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(4-phenylcyclohexyl) amino] cyclohexyl] -5-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one;

1- [4 - [(5-methylhex-2-yl) amino] cyclohexyl] -7-carbamoyl-1,3-dihydro-2H-benzimidazol-2-one; and

its pharmaceutically acceptable salts.

81. A pharmaceutical composition comprising a compound according to claim 63 and at least one pharmaceutically acceptable excipient.

82. A method of treating pain, comprising administering to a patient in need thereof an effective amount of an analgesic compound according to claim 63.

83. A method of modulating the pharmacological response from the ORL1 receptor, comprising administering to a patient in need thereof an effective amount of a compound according to claim 63.

84. A pharmaceutical composition comprising a compound according to claim 69 and at least one pharmaceutically acceptable

excipient.

85. A method of treating pain, comprising administering to a patient in need thereof an effective amount of an analgesic compound according to Claim 69.

86. A method of modulating the pharmacological response from the ORL1 receptor, comprising administering to a patient in need thereof an effective amount of a compound according to claim 69.

87. The compound of formula (IIIA):

where n represents an integer from 0 to 3;

ZR ₁ represents

or

R ₅ represents 1-3 substituents independently selected from

a group consisting of hydrogen, halogen, (C ₁ -C ₆ ) alkyl, R ₁₃ -aryl, (C ₃ -C ₁₂ ) cycloalkyl, -CN, -CF ₃ , -OR ₈ , - (C ₁ -C ₆ ) alkyl-OR ₈ , -OCF ₃ , -NR ₈ R ₉ , - (C ₁ -C ₆ ) alkyl-NR ₈ R ₉ , -NHSO ₂ R ₈ , -SO ₂ N (R ₁₄ ) ₂ , -NO ₂ , -CONR ₈ R ₉ , -NR ₉ COR ₈ , -COR ₈ , -OCOR ₈ , -OCO ₂ R ₈ and -COOR ₈ ;

or its pharmaceutically acceptable salts.

88. A pharmaceutical composition comprising a compound of claim 87 and at least one pharmaceutically acceptable excipient.

89. A method of treating pain, comprising administering to a patient in need thereof an effective amount of an analgesic compound according to Claim 87.

90. A method for modulating the pharmacological response from the ORL1 receptor, comprising administering to a patient in need thereof an effective amount of a compound of claim 87.

91. A method of modulating the pharmacological response from an opioid receptor, comprising administering to a patient in need thereof an effective amount of a compound according to claim 63.

92. A method of modulating the pharmacological response from an opioid receptor, comprising administering to a patient in need

in this, an effective amount of the compound of claim 69.

93. A method of modulating the pharmacological response from an opioid receptor, comprising administering to a patient in need thereof an effective amount of a compound of claim 87.

94. The compound of formula (IV):

where R represents hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _3-12 cycloalkyl C _1-4 alkyl, C _1-10 alkoxy, C _3-12 cycloalkoxy, C _1-10 alkyl, substituted 1- 3 halogens, C _3-12 cycloalkyl substituted with 1-3 halogens, C _3-12 cycloalkyl C _1-4 alkyl, substituted with 1-3 halogens, C _1-10 alkoxy, substituted with 1-3 halogens, C _3-12 cycloalkoxy substituted with 1-3 halogens, -COOV ₁ , -C _1-4 COOV ₁ , -CH ₂ OH, -SO ₂ N (V ₁ ) ₂ , hydroxyC _1-10 alkyl-, hydroxyC _3-10 cycloalkyl-, cyanoC _{1 -10} alkyl, cyanoC _3-10 cycloalkyl-, -CON (V ₁ ) ₂ , NH ₂ SO ₂ C _1-4 alkyl, NH ₂ SOC _1-4 alkyl, sulfonylamino C _1-10 alkyl, diaminoalkyl, -sulfonyl C _1-4 alkyl, 6-membered gete cyclic ring, 6 membered heteroaromatic ring, 6 membered heterocyclyl C _1-4 alkyl, 6 membered heteroaryl C _1-4 alkyl, 6 membered

aromatic ring, 6-membered _aryl C _1-4 alkyl, 5-membered heterocyclic ring, optionally substituted oxo or thio, 5-membered heteroaromatic ring, 5-membered heterocyclyl C _1-4 alkyl, optionally substituted oxo or thio, 5-membered heteroaryl C _1-4 alkyl-, -C _1-5 (= O) W ₁ , -C _1-5 (= NH) W ₁ , -C _1-5 NHC (= O) W ₁ , -C _1-5 NHS (= O) ₂ W ₁ , -C _1-5 NHS (= O) W ₁ , where W ₁ represents hydrogen, C _1-10 alkyl, C _3-12 cycloalkyl, C _1-10 alkoxy, C _3-12 cycloalkoxy , —CH ₂ OH, amino, C _1-4 alkylamino, diC _1-4 alkylamino or 5 membered heteroaromatic ring, optionally substituted with 1-3 lower alkyls;

n represents an integer from 0 to 3;

Z is selected from the group consisting of a bond, straight or branched C _1-6 alkylene, —NH—, —CH ₂ O—, —CH ₂ NH—, —CH ₂ N (CH ₃ ) -, —NHCH ₂ -, - CH ₂ CONH-, -NHCH ₂ CO-, -CH ₂ CO-, -COCH ₂ -, -CH ₂ COCH ₂ -, -CH (CH ₃ ) -, -CH =, -O- and -HC = CH- where carbon and / or nitrogen atoms

are unsubstituted or substituted by one or more lower alkyl, hydroxy, halogen or alkoxy groups;

where X ₁ and X _{2 are} independently selected from the group consisting of NH, O, S, and CH ₂ ; and wherein said alkyl, cycloalkyl, alkenyl, C _1-10 alkylamino, C _3-12 cycloalkylamino or benzyl from the group R _{1 is} optionally substituted with 1-3 substituents selected from the group consisting of halogen, hydroxy, C _1-10 alkyl , C _1-10 alkoxy, nitro, trifluoromethyl-, cyano, -COOV ₁ , -C _1-4 COOV ₁ , cyanoC _1-10 alkyl-, -C _1-5 (= O) W ₁ , -C _1-5 NHS (= O) ₂ W ₁ , -C _1-5 NHS (= O) W ₁ , 5-membered heteroaryl C _0-4 alkyl-, phenyl, benzyl, benzyloxy, wherein said phenyl, benzyl and benzyloxy are optionally substituted with 1- 3 substituents selected from the group consisting of halogen, C _1-10 alkyl-, C _1-10 alkoxy and cyano; and where indicated

C _3-12 cycloalkyl, C _3-12 cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring, heteromonocyclic ring, heterobicyclic ring system and spiro ring system of formula (V) are optionally substituted with 1-3 substituents selected from the group consisting of halogen, C _1-10 alkyl, C _1-10 alkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxy or benzyloxy are optionally substituted with 1-3 substituents selected from the group consisting of halogen , C _1-10 alkyl, C _1-10 alkoxy and cyano;

or its pharmaceutically acceptable salts or solvates.

95. The compound according to clause 94, in which D represents phenyl or a 6-membered heteroaromatic group containing 1-3 nitrogen atoms.

96. The compound of claim 94, wherein R is selected from the group consisting of —CH ₂ C = ONH ₂ , —C (NH) NH ₂ , pyridylmethyl, cyclopentyl, cyclohexyl, furanylmethyl, —C = OCH ₃ , —CH ₂ CH ₂ NHC = OCH ₃ , —SO ₂ CH ₃ , CH ₂ CH ₂ NHSO ₂ CH ₃ , furanylcarbonyl-, methylpyrrolylcarbonyl-, diazolcarbonyl-, azolmethyl-, trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxooxazolmethyl- or diazolmethyl-.

97. The compound of claim 94, wherein ZR _{1 is} selected from the group consisting of cyclohexyl ethyl, cyclohexyl methyl, cyclopentyl methyl, dimethyl cyclohexyl methyl, phenylethyl,

pyrrolyl trifluoroethyl-, thienyl trifluoroethyl-, pyridylethyl-, cyclopentyl-, cyclohexyl-, methoxycyclohexyl-, tetrahydropyranyl-, propylpiperidinyl-, indolylmethyl-, pyrazolylpentyl-, thiazolylethyl-, phenyltroxyhexyl-hydroxy-ethyl, hydroxy-ethyl, hydroxy-ethyl, hydroxy-ethyl, hydroxy-ethyl, hydroxy-ethyl, hydroxy-ethyl, hydroxy, methyl .

98. The compound of claim 94, wherein at least one of ZR ₁ and R is selected from the group consisting of —CH ₂ COOV ₁ , tetrazolylmethyl-, cyanomethyl-, NH ₂ SO ₂ methyl-, NH ₂ SOmethyl-, aminocarbonylmethyl -, C _1-4 alkylaminocarbonylmethyl- and diC _1-4 alkylaminocarbonylmethyl-.

99. The compound of claim 94, wherein ZR ₁ is 3,3-diphenylpropyl, optionally substituted at 3 carbon atoms with a propyl group -COOV ₁ , tetrazolyl C _0-4 alkyl-, cyano-, aminocarbonyl-, C _1-4 alkylaminocarbonyl- or diC _1-4 alkylaminocarbonyl.

100. The compound of formula (IVA):

where n represents an integer from 0 to 3;

Z is selected from the group consisting of, —CH ₂ -, —NH—, —CH ₂ O—, —CH ₂ CH ₂ -, —CH ₂ NH—, —CH ₂ N (CH ₃ ) -, —NHCH ₂ -, -CH ₂ CONH-, -NHCH ₂ CO-, -CH ₂ CO-, -COCH ₂ -, -CH ₂ COCH ₂ -, -CH (CH ₃ ) -, -CH = and -HC = CH-, where the carbon and / or nitrogen atoms are unsubstituted or substituted by lower alkyl, halogen, hydroxy or alkoxy;

or its pharmaceutically acceptable salts.

101. The compound of claim 100, wherein R ₁ is alkyl selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, and hexyl.

102. The compound of claim 100, wherein R ₁ is cycloalkyl selected from the group consisting of cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and norbornyl.

103. The compound according to p, in which R ₁ represents tetrahydronaphthyl, decahydronaphthyl or dibenzocycloheptyl.

104. The compound according to p, in which R ₁ represents phenyl

or benzyl.

105. The compound of claim 100, wherein R ₁ is a bicyclic aromatic ring.

106. The compound of claim 105, wherein said bicyclic aromatic ring is indenyl, quinoline or naphthyl.

107. The compound of claim 100, wherein Z is a bond, methyl or ethyl.

108. The compound of claim 100, wherein n is 0.

109. The compound of claim 100, wherein X ₁ and X ₂ both represent O.

110. A compound selected from the group consisting of:

2-cyanoimino-3-ethyl-1- [1- (p-phenylbenzyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole;

2-cyanoimino-3-ethyl-1- [1- (p-benzyloxybenzyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole;

2-cyanoimino-3-ethyl-1- [1- (naphth-2-ylmethyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole;

2-cyanoimino-3-ethyl-1- [1- (4-propylcyclohexyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole;

2-cyanoimino-3-ethyl-1- [1- [4- (2-propyl) cyclohexyl] -4-piperidinyl] -1,3-dihydro-2H-benzimidazole;

2-cyanoimino-3-ethyl-1- [1- (decahydro-2-naphthyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole;

2-cyanoimino-3-ethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole;

2-cyanoimino-3-ethyl-1- [1- (10,11-dihydro-5H-

dibenzo [a, d] cyclohepten-5-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole;

2-cyanoimino-3-ethyl-1- [1- (3,3-bis (phenyl) propyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole;

2-cyanoimino-3-ethyl-1- [1- (1,2,3,4-tetrahydronaphthyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole;

2-cyanoimino-3-ethyl-1- [1- (5-methylhex-2-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole;

2-cyanoimino-3-ethyl-1- [1- (norbornan-2-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole;

2-cyanoimino-3-ethyl-1- [1- (1,3-dihydroinden-2-yl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole;

2-cyanoimino-3-ethyl-1- [1- (cyclooctylmethyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole; and

its pharmaceutically acceptable salts.

111. A compound selected from the group consisting of:

2-cyanoimino-3- (2-hydroxy) ethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole;

2-cyanoimino-3-methoxycarbonylmethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole;

2-cyanoimino-3-cyanomethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole;

2-cyanoimino-3-butyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole;

2-cyanoimino-3- (2-methanesulfonamido) ethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole;

2-cyanoimino-3-acetamido-1- [1- (cyclooctyl) -4-piperidinyl] -

1,3-dihydro-2H-benzimidazole;

2-cyanoimino-3-carboxymethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole;

2-cyanoimino-3- (2-dimethylamino) ethyl-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-benzimidazole;

2-cyanoimino-1- [1- (cyclooctyl) -3-hydroxymethyl-4-piperidinyl] -1,3-dihydro-2H-benzimidazole;

2-cyanoimino-1- [1- (cyclooctyl) -4-piperidinyl] -1,3-dihydro-2H-7-azabenzimidazole;

2-cyanoimino-1- [1- (cyclooctyl) -2,6-ethan-4-one-4-piperidinyl] -1,3-dihydro-2H-benzimidazole; and

its pharmaceutically acceptable salts and solvates.

112. A pharmaceutical composition comprising the compound of claim 94 and at least one pharmaceutically acceptable excipient.

113. A method of treating pain, comprising administering to a patient in need thereof an effective amount of an analgesic compound according to claim 94.

114. A method for modulating the pharmacological response from the ORL1 receptor, comprising administering to a patient in need thereof an effective amount of a compound according to claim 94.

115. A pharmaceutical composition comprising a compound according to claim 100 and at least one pharmaceutically acceptable excipient.

116. A method of treating pain, comprising administering to a patient in need thereof an effective amount of an analgesic compound according to claim 100.

117. A method of modulating the pharmacological response from the ORL1 receptor, comprising administering to a patient in need thereof an effective amount of a compound according to claim 100.

118. The compound of formula (IVA):

where n represents an integer from 0 to 3;

ZR ₁ represents

where Y ₁ represents R ₃ - (C ₁ -C ₁₂ ) alkyl, R ₄ aryl, R ₅ heteroaryl, R ₆ -

(C ₃ -C ₁₂ ) cycloalkyl, R ₇ - (C ₃ -C ₇ ) heterocycloalkyl, -CO ₂ (C ₁ -C ₆ ) alkyl, CN or –C (O) NR ₈ R ₉ ; Y ₂ represents hydrogen or Y ₁ ; Y ₃ represents hydrogen or (C ₁ -C ₆ ) alkyl; or Y ₁ , Y ₂ and Y ₃ together with the carbon atom to which they are bonded form one of the following structures:

or

R ₁₁ represents 1-3 substituents independently selected from the group consisting of R ₁₀ , —CF ₃ , —OCF ₃ , NO ₂ and halogen, or R ₁₁

substituents on adjacent ring carbon atoms together may form a methylenedioxy or ethylenedioxy ring;

R ₅ represents 1-3 substituents independently selected from the group consisting of hydrogen, halogen, (C ₁ -C ₆ ) alkyl, R ₁₃ aryl, (C ₃ -C ₁₂ ) cycloalkyl, —CN, —CF ₃ , - OR ₈ , - (C ₁ -C ₆ ) alkyl-OR ₈ , -OCF ₃ ,

-NR ₈ R ₉ , - (C ₁ -C ₆ ) alkyl-NR ₈ R ₉ , -NHSO ₂ R ₈ , -SO ₂ N (R ₁₄ ) ₂ , -NO ₂ , -CONR ₈ R ₉ , -NR ₉ COR ₈ , -COR ₈ , -OCOR ₈ , -OCO ₂ R ₈ and -COOR ₈ ;

and its pharmaceutically acceptable salts.

119. A pharmaceutical composition comprising the compound of Claim 118 and at least one pharmaceutically acceptable excipient.

120. A method of treating pain, comprising administering to a patient in need thereof an effective amount of an analgesic compound according to Claim 118.

121. A method of modulating the pharmacological response from the ORL1 receptor, comprising administering to a patient in need thereof an effective amount of a compound according to Claim 118.

122. A method of modulating the pharmacological response from an opioid receptor, comprising administering to a patient in need thereof an effective amount of a compound according to claim 94.

123. A method of modulating the pharmacological response from an opioid receptor, comprising administering to a patient in need thereof an effective amount of a compound according to claim 100.

124. A method for modulating the pharmacological response from

an opioid receptor, comprising administering to a patient in need thereof an effective amount of a compound according to claim 118.